Prostate cancer occurs frequently in men, is currently the second most common cause of cancer-related death and incidence is growing. Prostatectomy is useful in the treatment of patients with cancer confined to the prostate. Androgen ablation therapy is used in cases where cancer cells still require androgens for growth but have spread beyond the prostate. To date, however, there is no effective treatment for metastatic Androgen-independent Prostate Cancer (AIPC).
Our understanding of the aetiology of prostate cancer is limited and unlike certain other cancers, little progress has been made in elucidating its cause. Efforts have been made to identify genes responsible for familial prostate cancer. At least seven chromosomal loci have been reported, however the genes responsible for prostate cancer in all these loci have not yet been identified. Although an inherited genetic predisposition occurs in only 5-10% of cases, it is possible that identification of germline mutations may shed light on sporadic cases as both forms share the same histopathological features. The majority of researchers have focused on somatic defects in sporadic prostate cancer. Classical cytogenetic studies are difficult to apply to solid tumours and so far no consistent chromosomal changes have been observed. Although comparative genome hybridisation and loss of heterozygosity analysis have shown both gain and loss of genomic DNA, the majority of genes involved are still unknown. Oncogenes and tumour suppressor genes known to be associated with other malignancies have a remarkably low frequency of mutation or deletion in prostate cancer. Using technologies that compare the steady-state mRNA levels between normal and cancerous prostate, a list of genes have been revealed to be either over or underexpressed in prostate cancer tissue or cell-lines. Although proteomics and tissue array approaches are now being used, relatively few genes have yet been verified to be differentially expressed in a reasonable number of specimens at the protein level. Direct evidence for the importance of these differentially expressed genes in prostate cancer initiation or progression is lacking. As a result, although progress is rapid, the application of this new knowledge in controlling mortality and morbidity from prostate cancer is slow at present.
Emerging evidence from epidemiological studies indicates a strong association between prostate cancer risk and total fat intake (Kolonel et al., 1999 J. Natl Cancer Inst. 91: 414), although the biochemical link between dietary lipids and genesis of prostate cancer remains unclear. Previous studies have demonstrated that both cyclooxygenase (COX) and lipoxygenase (LOX) products of arachidonic acid metabolism, the prostaglandins (PG), and hydroxyeicosatetraenoic acids (HETES) respectively, contribute to formation and/or progression of prostate cancer. They are implicated in promotion of tumour cell proliferation, motility, invasion and metastasis, and induction of angiogenesis both in vitro and in animal models. Interestingly, arachidonic acid levels are lower in malignant than benign (BPH) prostate tissue while PG and HETE synthesis from labelled arachidonic acid is significantly increased. However, the activity of arachidonic acid mobilising enzymes phospholipase A2 (PLA2) and fatty acyl-CoA lysophosphatidylcholine acyltransferase, are also increased, suggesting an increased flux of arachidonic acid through the COX and LOX pathways.
PLA2 constitutes a large and diverse family of enzymes that catalyse the hydrolysis of membrane phospholipids at the sn-2 position to release fatty acids and lysophospholipids. PLA2 enzymes are classified according to their source and their cellular location (i.e secreted PLA2 enzymes (sPLA2s) or cytosolic PLA2 enzymes (cPLA2s)). A review of the classification and characterisation of the expanding superfamily of PLA2 enzymes had been published by Six and Dennis (2000) Biochim. Biophys. Acta 1488:1-19.
sPLA2-IIA is elevated in prostate cancer (Graff et al., 2001, Clin. Cancer Res. 7: 3857-3861; Jiang et al., 2002, Am. J. Pathol. 160: 667-671) and enhanced sPLA2-IIA expression has been inversely related to 5-year patient survival (Graff et al., 2001). In addition, the chromosomal location of several sPLA2 genes including sPLA2-IIA (1p35-ter), overlaps with one prostate cancer susceptibility locus CAPB (Nwosu et al., 2001, Human Mol. Genet. 10: 2313-2318). To date, however, there has been no evidence to show that sPLA2-IIA is involved in prostate tumorigenesis.